Methamphetamine (METH) is a highly addictive psychomotorstimulant. Repeated administration of METH elicits neuroadaptations that last long after drug-taking ceases. These adaptations contribute to compulsive drug-seeking and relapse in the withdrawn addict, phenomena that are particularly compelling when the addict is faced with people, places or things that were associated with their drug use. The purpose of this project is to investigate 5-HT2 receptors (5-HT2R) and an associated signaling protein, GSKSbeta, as possible new medication targets for METH abuse. METH-induced conditioned place preference (CPP) in rats will be used to efficiently model aspects of human drug use. As addiction therapy will need to be effective after one becomes addicted, we plan to evaluate the treatment targets in rats already expressing METH-induced CPP. We provide Preliminary Data where METH-conditioning can be reversed with mirtazapine, an antidepressant with high affinity for 5-HT2 receptors. The overall hypothesis for this grant is that 5-HT2 antagonists will disrupt the maintenance of the drug-reward memory and will compensate and/or reverse the neuroadaptations elicited in METH-conditioned rats. Three hypothesis-driven Specific Aims are proposed. Aim I Hypothesis: Systemic administration of 5-HT2R antagonists, and/or an inhibitor of GSKSbeta, to METH-conditioned rats will dose-dependently attenuate subsequent preference for the METH- paired context. Aim II Hypothesis: Attenuation of persistent METH-induced CPP will correlate with increased surface expression of AMPA receptors and levels of GSKSbeta phosphorylated at the serine 9 position. We will use a novel cross-linking assay to determine changes in AMPA receptor trafficking and immunoblot procedures to detect the phosphorylation state of GSKSbeta. Aim III Hypothesis: METH- conditioned rats will enhance AMPA-mediated excitability of neurons in those regions where AMPAR surface expression was elevated (determined in Aim II). This will be assessed by whole-cell patch clamp electrophysiology. Using a rodent model of human addiction provides opportunity to engage in translational research that will expand our understanding of the molecular mechanisms underlying METH addiction, and suggest a novel addiction treatment strategy. This NRSA grant will also allow the applicant exciting new training opportunities in the neuroscience of addiction. In summary, METH abuse is a serious problem in the United States, with no current effective treatment programs. The goal of this proposal is to help identify potential "anti-addiction" medications that will support recovery from METH addiction.